Understanding Pain in hEDS

See below for Low-Dose Naltrexone

Chronic pain is one of the most common and disabling symptoms of hypermobile Ehlers-Danlos syndrome (hEDS). More than 80–90% of people with hEDS develop persistent pain, often beginning during childhood or adolescence and becoming more widespread over time. For many, pain has the greatest impact on daily activities, employment, school, sleep, relationships, and overall quality of life.

Unlike pain caused by a single injury or disease, pain in hEDS usually results from multiple overlapping mechanisms. Joint instability, repeated soft tissue injuries, muscle overuse, arthritis, neuropathic pain, small fiber neuropathy, central sensitization, headaches, gastrointestinal disorders, and associated conditions such as dysautonomia and mast cell activation syndrome (MCAS) may all contribute simultaneously. As a result, no two people with hEDS experience pain in exactly the same way.

This complexity also explains why pain management can be frustrating. A treatment that is highly effective for one type of pain may provide little benefit for another because the underlying pain mechanisms are different. Successful treatment begins by identifying the factors contributing to an individual's pain and selecting therapies that target those specific mechanisms.

Rather than focusing on a single treatment, this article explains why pain occurs in hEDS, reviews the major types of pain, and discusses the evidence supporting the treatments used to manage them. Topics such as physical therapy, pacing, assistive devices, sleep, psychological health, dysautonomia, mast cell activation syndrome, low-dose naltrexone, and complementary therapies each have dedicated articles elsewhere on this website and are introduced here only as they relate directly to pain.

On This Page

• Understanding the Evidence

• Why Is Pain So Common in hEDS?

• Types of Pain

• Principles of Pain Management

• Medications for Pain

• Behavioral and Psychological Approaches

• Complementary and Non-Medication Treatments

• Advanced and Specialized Pain Management

• Surgery

• Summary

Understanding the Evidence

Compared with many chronic pain conditions, relatively little research has been conducted specifically in people with hEDS. As a result, this article distinguishes between

• Evidence-supported treatments based on high-quality scientific studies.

• Treatments supported by current scientific understanding and clinical experience, even when hEDS-specific studies are limited.

• Emerging therapies that appear promising but require additional research.

A lack of hEDS-specific research does not necessarily mean that a treatment is ineffective. In many cases, it simply reflects the need for more research.

Why Is Pain So Common in hEDS?

Pain in hEDS rarely has a single cause. Instead, abnormalities of connective tissue affect multiple body systems, creating several pain mechanisms that often occur simultaneously and reinforce one another.

For most people, the process begins with joint instability. Ligaments that are unable to adequately stabilize joints allow excessive movement, forcing surrounding muscles to work continuously to compensate. Over time, this increased workload can result in

• Muscle fatigue

• Tendon injuries

• Painful trigger points

• Recurrent sprains

• Joint subluxations and dislocations

Repeated injuries may also irritate peripheral nerves or contribute to the development of small fiber neuropathy. As pain persists, the brain and spinal cord may become increasingly sensitive through a process known as central sensitization, causing pain to become more widespread and more intense than would be expected from the original injury.

Several associated conditions can further amplify pain by increasing nervous system sensitivity or reducing the body's ability to recover. These include

• Dysautonomia

• Mast cell activation syndrome (MCAS)

• Poor sleep

• Gastrointestinal disorders

• Anxiety and depression

• Physical deconditioning

Rather than acting independently, these problems often create a self-perpetuating cycle. Joint instability leads to repeated tissue injury, tissue injury contributes to persistent pain, persistent pain promotes central sensitization, and central sensitization further amplifies future pain. Poor sleep, fatigue, autonomic dysfunction, and other associated conditions can intensify this cycle even further.

Understanding these overlapping pain mechanisms is one of the most important concepts in hEDS because it explains why successful treatment almost always requires a multimodal approach. Medications, rehabilitation, pacing, assistive devices, treatment of associated medical conditions, and lifestyle strategies each address different contributors to pain, and no single treatment is effective for every type of pain.

Types of Pain in hEDS

Understanding the different types of pain experienced in hEDS is essential because each responds to different treatments.

Most people with hEDS experience several of these pain mechanisms simultaneously. For example, one person may have joint instability, myofascial pain, small fiber neuropathy, and central sensitization all contributing to their symptoms. Because each responds differently to treatment, successful pain management usually requires a combination of therapies rather than relying on a single medication or intervention.

Musculoskeletal Pain

Musculoskeletal (mechanical) pain is the most common type of pain experienced by people with hEDS and is often the first symptom to develop.

Unlike inflammatory conditions, mechanical pain results from excessive movement of unstable joints. Ligaments that are too lax to adequately stabilize joints place abnormal stress on muscles, tendons, joint capsules, and other soft tissues. Over time, these repeated stresses can produce chronic pain even without a major injury.

Musculoskeletal pain commonly affects the

• Knees

• Shoulders

• Hips

• Ankles

• Feet

• Hands and wrists

• Neck

• Lower back

Mechanical pain typically worsens with prolonged standing, repetitive activity, or sustained positions and often improves with rest, pacing, joint support, or appropriately designed strengthening exercises.

Although joint instability is the primary cause, secondary problems frequently develop over time, including tendon injuries, bursitis, muscle overuse, trigger points, and early osteoarthritis.

Myofascial Pain

Myofascial pain originates in muscles and the connective tissue (fascia) surrounding them. It is one of the most common—and often overlooked—sources of pain in hEDS.

Because muscles must continually compensate for unstable joints, they work much harder than they do in people without hEDS. Over time, this constant workload may lead to fatigue, painful trigger points, muscle tightness, and chronic aching.

People with myofascial pain often describe

• Deep, aching muscles

• Tender "knots" within muscles

• Muscle stiffness

• Pain that radiates into nearby areas

• Pain that increases after prolonged activity or remaining in one position

Research supports strengthening and rehabilitation as the cornerstone of treatment because improving muscle endurance reduces the burden placed on overworked muscles. Massage, trigger point therapy, heat, and other manual therapies may also help some individuals, although research specific to hEDS remains limited. These treatments are discussed in greater detail in the Alternative & Non-medication Treatments article.

Arthritis

People with hEDS have an increased risk of developing both osteoarthritis and inflammatory arthritis.

Osteoarthritis develops because years of abnormal joint movement gradually wear away cartilage. This process may occur earlier than expected because unstable joints distribute forces unevenly across the joint surface.

IAlthough hEDS does not cause inflammatory arthritis, inflammatory conditions such as rheumatoid arthritis and spondyloarthropathies (a group of inflammatory conditions that affect the spine and other joints, including ankylosing spondylitis and psoriatic arthritis) appear to occur more frequently in people with hEDS than in the general population.

Features that suggest inflammatory arthritis rather than mechanical pain include

• Persistent joint swelling

• Warmth or redness of a joint

• Prolonged morning stiffness

• Elevated inflammatory markers

• Progressive joint damage unrelated to instability

Because treatment differs substantially, persistent inflammatory symptoms should be evaluated by a rheumatologist.

Neuropathic Pain

Not all pain in hEDS comes from joints and muscles. Increasing evidence shows that dysfunction of the nervous system itself contributes to chronic pain in many people with hEDS.

Neuropathic pain is commonly described as

• Burning

• Shooting

• Stabbing

• Electric shock-like

• Tingling

• Pins-and-needles sensations

This type of pain may occur when unstable joints stretch or compress peripheral nerves. It may also result from small fiber neuropathy, which has emerged as one of the most important neurological contributors to pain in hEDS.

Small Fiber Neuropathy

Small fiber neuropathy (SFN) affects the small nerve fibers responsible for transmitting pain and temperature sensations and regulating many autonomic functions.

Over the past decade, multiple studies have demonstrated reduced small nerve fiber density in many people with hEDS and hypermobility spectrum disorders. Although researchers continue to investigate this relationship, small fiber neuropathy is now recognized as an important contributor to pain in a substantial proportion of patients.

Symptoms may include

• Burning pain

• Tingling or numbness

• Electric shock-like sensations

• Increased sensitivity to touch or temperature

• Pain from normally non-painful stimuli (allodynia)

• Dysautonomic symptoms

Routine nerve conduction studies and electromyography (EMG) are frequently normal because they evaluate large nerve fibers rather than the small fibers affected in small fiber neuropathy. When clinically indicated, a skin biopsy measuring intraepidermal nerve fiber density is currently considered the diagnostic standard.

Central Sensitization

One of the most important advances in chronic pain research has been the recognition of central sensitization.

Normally, pain decreases as tissues heal. In central sensitization, however, the brain and spinal cord become increasingly sensitive to pain signals, causing pain to become more widespread, more intense, and more persistent than would be expected from the original injury.

Central sensitization does not mean that pain is psychological or imagined. It reflects measurable changes in how the nervous system processes pain and helps explain why chronic pain sometimes continues even after the original tissue injury has improved.

People with central sensitization commonly experience

• Widespread pain

• Increased pain sensitivity

• Pain from normally non-painful stimuli (allodynia)

• Heightened responses to painful stimuli (hyperalgesia)

• Fatigue

• Non-restorative sleep

• Brain fog

Central sensitization also helps explain why treating only the painful joint often provides incomplete relief. Improving sleep, gradually increasing physical activity, treating associated medical conditions, and using medications that target abnormal pain processing may all reduce pain amplification.

Other Sources of Pain

Pain in hEDS is not limited to the musculoskeletal or nervous systems. Many people also experience headaches, abdominal pain, pelvic pain, chest wall pain, and pain associated with other medical conditions.

In addition, several common comorbidities—including dysautonomia, mast cell activation syndrome (MCAS), gastrointestinal disorders, poor sleep, anxiety, and depression—can increase pain sensitivity and make existing pain more difficult to control.

Because these conditions are discussed in detail elsewhere on this website, they are not reviewed further here. Recognizing and treating associated conditions is often an important part of successful pain management, even when they are not the primary source of pain.

Understanding the underlying source—or, more commonly, sources—of pain is the first step in choosing effective treatment. The next section reviews the general principles of pain management before discussing specific medications and other treatment options.

Principles of Pain Management

Because pain in hEDS usually arises from multiple overlapping mechanisms, successful treatment rarely depends on a single therapy. Instead, the goal is to identify the factors contributing to an individual's pain and select treatments that target each of those mechanisms.

For example, medications may reduce neuropathic pain or inflammation, physical therapy may improve joint stability, pacing may decrease repeated tissue injury, and treating associated conditions such as poor sleep or dysautonomia may reduce pain amplification. Each treatment addresses a different part of the problem.

Finding an effective treatment plan often requires patience and some trial and adjustment. Two people with hEDS may have similar symptoms but respond very differently to the same treatment because the underlying pain mechanisms are not identical.

The ultimate goals of treatment are to

• Reduce pain

• Improve physical function

• Prevent recurrent injuries

• Increase independence

• Improve quality of life

Managing Pain Flares

Even with a well-designed treatment plan, most people with hEDS experience temporary increases in pain. These pain flares may last from hours to several weeks and are commonly triggered by

• Increased physical activity

• Joint injuries or overuse

• Illness

• Poor sleep

• Emotional stress

• Hormonal changes

• Weather changes (commonly reported by patients, although scientific evidence remains mixed)

Pain flares do not necessarily indicate that permanent damage has occurred. More often, they reflect temporary increases in tissue irritation, muscle guarding, joint instability, nervous system sensitization, or several of these occurring together.

During a flare, it is often helpful to

• Temporarily reduce activities that substantially increase pain

• Continue gentle movement rather than prolonged bed rest

• Resume normal activities gradually as symptoms improve

• Use pacing strategies to avoid the "boom-and-bust" cycle

• Apply heat or ice, depending on the source of pain

• Temporarily use braces or splints if they have previously been helpful

• Prioritize sleep, hydration, and good nutrition

• Use medications as recommended by your healthcare provider

Many people with hEDS also report benefit from heated blankets, warm baths, aquatic exercise, topical pain-relieving products, and other comfort measures during flares. Although these approaches have not been well studied specifically in hEDS, they are generally low risk and may be worthwhile if they provide relief.

Pain that is accompanied by fever, marked swelling, inability to bear weight, new neurological symptoms, or other symptoms that differ substantially from previous flares should prompt medical evaluation.

Practical strategies for reducing pain flares are discussed in greater detail in the Pacing article.

Rehabilitation

Rehabilitation is the foundation of long-term pain management because it addresses one of the primary causes of pain in hEDS: joint instability.

Research supports progressive strengthening, proprioceptive training, and individualized exercise programs for improving function and reducing pain in people with hypermobility disorders. Rather than simply masking pain, rehabilitation aims to improve joint stability, movement efficiency, and muscle endurance so that painful injuries become less frequent over time.

Physical therapy is only one part of rehabilitation. Learning how to pace activities, protect unstable joints, modify daily tasks, and gradually increase strength and endurance are equally important for long-term success.

Because these topics are covered extensively elsewhere on this website, they are discussed only briefly here.

Assistive Devices

Braces, splints, orthotics, compression garments, and mobility aids can reduce pain, improve stability, conserve energy, and help people remain active.

Although relatively little research has evaluated these devices specifically in hEDS, they are widely recommended by clinicians experienced in treating hypermobility disorders and are frequently reported by patients to improve comfort and function.

Choosing the right device depends on the joints involved, the degree of instability, and an individual's daily activities. Detailed guidance is provided in the Assistive Devices article.

Medications for Pain

Medications are an important part of pain management for many people with hEDS, but they work best when combined with rehabilitation and other non-medication strategies.

No medication corrects the underlying connective tissue disorder. Instead, different medications target different pain mechanisms. For example, anti-inflammatory medications work best for inflammatory pain, while other medications are more effective for neuropathic pain or central sensitization.

The following sections summarize the medications most commonly used for pain in hEDS. Each section describes the types of pain for which the medication is most useful, the evidence supporting its use, important considerations for people with hEDS, and the most common side effects.

Acetaminophen

Acetaminophen (Tylenol®) is commonly recommended as a first-line medication for mild musculoskeletal pain. Although it has little anti-inflammatory activity, it is generally well tolerated and can be useful for mild pain or as one component of a broader pain management plan.

Best for

• Mild mechanical (musculoskeletal) pain

• Mild osteoarthritis pain

• Short-term pain relief when inflammation is not the primary problem

• People who cannot take NSAIDs because of stomach, kidney, or bleeding concerns

Current Evidence

Acetaminophen is considered a reasonable first-line option for mild musculoskeletal pain because it

• Does not affect platelet function

• Does not increase bruising

• Does not weaken muscles

• Does not worsen joint instability

• Has a favorable safety profile when used as directed

Its effectiveness is greatest for mild mechanical pain. It is much less helpful for neuropathic pain, central sensitization, or widespread chronic pain.

Like all medications, acetaminophen has risks. Excessive doses can cause serious liver injury, particularly in people with liver disease or those who regularly consume alcohol.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs reduce pain by decreasing inflammation. They are most effective when inflammation is an important contributor to pain.

Common over-the-counter examples include ibuprofen (Advil®, Motrin®) and naproxen (Aleve®). Frequently prescribed NSAIDs include meloxicam (Mobic®), diclofenac (Voltaren®), nabumetone (Relafen®), celecoxib (Celebrex®), etodolac (Lodine®), and indomethacin (Indocin®).

Best for

• Acute sprains and strains

• Pain following subluxations or dislocations

• Tendinitis

• Bursitis

• Costochondritis

• Inflammatory arthritis

Current Evidence

NSAIDs are effective when inflammation is a significant contributor to pain. However, many people with hEDS find that they provide only modest relief for chronic pain because much of the pain associated with hEDS results from joint instability, muscle overuse, neuropathic pain, and central sensitization rather than ongoing inflammation.

Potential side effects include stomach irritation or bleeding, kidney injury, increased blood pressure, and increased cardiovascular risk with prolonged use. COX-2 inhibitors, such as celecoxib, generally cause fewer gastrointestinal side effects than traditional NSAIDs, although cardiovascular risks remain an important consideration.

Easy bruising alone is not considered a contraindication to NSAID therapy in hEDS. However, because connective tissue fragility may increase bruising or mucosal bleeding in some individuals, treatment should be individualized. Aspirin is generally avoided for routine pain management unless there is another medical indication because it permanently affects platelet function.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Among currently available medications, duloxetine (Cymbalta®) has some of the strongest evidence for treating several pain mechanisms commonly seen in hEDS.

Although studies specifically evaluating duloxetine in hEDS remain limited, it is recommended in several EDS management guidelines and by GeneReviews as part of an individualized approach to chronic pain management.

Best for

• Chronic musculoskeletal pain

• Neuropathic pain

• Central sensitization

• Fibromyalgia-type widespread pain

• Chronic pain accompanied by anxiety or depression

Current Evidence

Large clinical trials involving people with chronic musculoskeletal pain, fibromyalgia, and neuropathic pain have shown that duloxetine

• Reduces pain

• Improves physical functioning

• Improves quality of life

• Reduces neuropathic pain

• Improves fibromyalgia-related pain

Importantly, research shows that duloxetine's pain-relieving effects are largely independent of its antidepressant effects, meaning it functions as both a pain medication and an antidepressant.

Current understanding of pain in hEDS also suggests that duloxetine is particularly well suited to many patients because it targets several common pain mechanisms simultaneously. Unlike muscle relaxants, it does not reduce muscle tone or worsen joint instability.

Another SNRI, venlafaxine (Effexor®), may also help neuropathic pain. Because it can modestly increase blood pressure, it may be useful for some individuals with neurally mediated hypotension, although this effect is usually small.

Common side effects include

• Nausea

• Dizziness

• Sleepiness

• Dry mouth

• Constipation

• Mild increases in blood pressure

Many of these side effects improve during the first few weeks of treatment.

Tricyclic Antidepressants (TCAs)

Tricyclic antidepressants have been used for chronic pain management for decades and remain effective medications for selected patients.

Commonly prescribed medications include amitriptyline (Elavil®), nortriptyline (Pamelor®), and desipramine (Norpramin®).

Best for

• Neuropathic pain

• Fibromyalgia-type pain

• Migraine prevention

• Chronic headaches

• Chronic pain associated with poor sleep

Current Evidence

Research supports the use of tricyclic antidepressants for several chronic pain conditions, particularly neuropathic pain and migraine prevention. For some neuropathic pain conditions, they remain among the most effective medications available.

Despite their effectiveness, side effects often limit their use in people with hEDS. These may include

• Dry mouth

• Constipation

• Blurred vision

• Urinary retention

• Weight gain

• Daytime sleepiness

• Dizziness

• Cognitive slowing

Because many people with hEDS also have dysautonomia or postural orthostatic tachycardia syndrome (POTS), tricyclic antidepressants may worsen orthostatic hypotension. Nortriptyline and desipramine are generally better tolerated than amitriptyline in this regard.

Gabapentinoids

Gabapentin (Neurontin®) and pregabalin (Lyrica®) reduce abnormal nerve signaling and are commonly prescribed when neuropathic pain contributes to symptoms.

Best for

• Neuropathic pain

• Burning pain

• Electric shock-like pain

• Tingling or pins-and-needles sensations

• Small fiber neuropathy

• Sleep disturbance related to neuropathic pain

Current Evidence

Gabapentinoids have demonstrated benefit for several neuropathic pain conditions outside of hEDS and are commonly used when burning pain, tingling, allodynia, or small fiber neuropathy is suspected.

Evidence specific to hEDS is much more limited. Some studies suggest modest benefit, while others report relatively poor effectiveness. Clinical experience is similarly mixed. Some people with hEDS experience substantial improvement, particularly when small fiber neuropathy contributes to their pain, while others find little benefit or discontinue treatment because of side effects.

Common side effects include

• Dizziness

• Sleepiness

• Brain fog

• Peripheral edema (swelling)

• Weight gain

Because dizziness, fatigue, and cognitive symptoms are already common in hEDS, these medications may be more difficult for some people to tolerate.

Muscle Relaxants

Muscle relaxants are commonly prescribed for acute muscle spasms but have a limited role in the long-term management of hEDS.

Common examples include cyclobenzaprine (Flexeril®), tizanidine (Zanaflex®), methocarbamol (Robaxin®), baclofen (Lioresal®), metaxalone (Skelaxin®), and carisoprodol (Soma®).

Best for

• Acute muscle spasms

• Severe muscle guarding following an injury

• Pain after a joint subluxation or dislocation

Current Evidence

Unlike many chronic pain conditions, muscles in hEDS provide essential stability for hypermobile joints. Medications that reduce muscle tone may therefore increase joint instability and, paradoxically, worsen pain over time.

Current evidence does not support long-term use of muscle relaxants for chronic musculoskeletal pain, and several EDS management guidelines caution against prolonged use because reducing compensatory muscle support may increase instability.

Common side effects include

• Sleepiness

• Dizziness

• Fatigue

• Impaired concentration

These side effects may compound symptoms already experienced by many people with hEDS.

Low-Dose Naltrexone

Low-dose naltrexone (LDN) is an emerging treatment that appears to work differently from traditional pain medications by reducing neuroinflammation through modulation of microglial cells within the central nervous system.

Best for

• Central sensitization (possible)

• Fibromyalgia-type pain (possible)

• Widespread chronic pain (possible)

• People interested in emerging treatment options

Current Evidence

Research on LDN remains mixed. Some studies suggest benefit for centralized pain conditions, while others—including a recent study in fibromyalgia—have not demonstrated clinically meaningful improvement over placebo.

Despite the limited evidence, LDN continues to generate considerable interest because it has a plausible biological basis, is generally well tolerated, and many clinicians and patients report meaningful improvements in pain, fatigue, or both. At present, however, it should be considered a promising but still emerging therapy rather than an established treatment.

Because LDN is discussed in much greater detail elsewhere in this article, a separate section reviews the current research, potential benefits, limitations, and practical considerations.

See the article below for a more complete discussion.

Opioids

Opioids are generally reserved for severe pain that has not responded adequately to safer treatments. Whenever possible, treatment should first optimize rehabilitation, pacing, treatment of associated medical conditions, and non-opioid medications.

Best for

• Severe acute pain

• Carefully selected cases of severe chronic pain that have not responded to other treatments

Current Evidence

Opioids can provide meaningful short-term relief for acute pain and may occasionally be appropriate for carefully selected individuals with severe chronic pain. However, long-term use carries substantial risks, including

• Tolerance

• Physical dependence

• Constipation

• Hormonal changes

• Fatigue

• Cognitive impairment

• Falls

• Respiratory depression

• Opioid-induced hyperalgesia

One of the most important concerns is opioid-induced hyperalgesia (OIH), a paradoxical condition in which prolonged opioid use increases pain sensitivity rather than reducing it. This may be particularly relevant in hEDS because many people already have central sensitization.

For these reasons, current recommendations emphasize multimodal pain management and careful consideration of the risks and benefits before long-term opioid therapy is prescribed.

Topical Medications

Topical medications are often overlooked but can provide effective localized pain relief while minimizing whole-body side effects. They are particularly useful when pain is confined to a specific joint, tendon, trigger point, or small area of neuropathic pain.

Topical NSAIDs

Examples include diclofenac (Voltaren®) gel and diclofenac patches.

Best for

• Localized joint pain

• Tendon injuries

• Ligament injuries

• Mild osteoarthritis

• Soft tissue injuries

Current Evidence

Topical NSAIDs have strong evidence supporting their use for localized musculoskeletal injuries and osteoarthritis. Because only a small amount of medication enters the bloodstream, they carry much lower risks of gastrointestinal bleeding, kidney injury, and cardiovascular complications than oral NSAIDs.

Topical Lidocaine

Examples include lidocaine creams and 5% patches.

Best for

• Localized neuropathic pain

• Painful trigger points

• Focal nerve irritation

• Areas of allodynia

Current Evidence

Topical lidocaine may reduce localized neuropathic pain with very few systemic side effects. Although research specific to hEDS is limited, GeneReviews includes topical lidocaine as a treatment option because of its favorable safety profile.

Topical Capsaicin

Best for

• Localized neuropathic pain

• Selected chronic pain conditions

Current Evidence

Capsaicin reduces pain by decreasing the activity of pain-sensing nerve endings. Prescription-strength capsaicin patches have demonstrated benefit for several neuropathic pain conditions, while lower-strength over-the-counter creams have weaker supporting evidence but may still provide relief for some individuals.

Temporary burning, redness, and skin irritation are common when treatment is first started.

Other Topical Treatments

Examples include menthol-containing creams and gels, CBD creams, compounded topical medications, and topical magnesium products.

Best for

• Localized muscle pain

• Mild joint pain

• Adjunctive treatment alongside other therapies

Current Evidence

These products have little or no direct scientific evidence in hEDS, but they are generally low risk and may be reasonable to try for localized pain after discussing them with a healthcare provider.

Matching Pain Mechanisms to Treatments

Because different pain mechanisms respond to different treatments, identifying the type—or, more commonly, the combination of types—of pain is one of the most important steps in developing an effective treatment plan.

Most people with hEDS experience several of these pain mechanisms simultaneously. As a result, successful pain management usually combines multiple treatments that target different contributors to pain rather than relying on a single medication or therapy.

Behavioral and Psychological Approaches

Living with chronic pain can affect nearly every aspect of life, including sleep, mood, relationships, work, school, and participation in enjoyable activities. At the same time, poor sleep, stress, anxiety, depression, and reduced activity can further increase pain sensitivity by affecting how the nervous system processes pain.

Behavioral and psychological therapies do not imply that pain is psychological or "all in your head." Rather, they are evidence-based treatments that help people manage the effects of chronic pain, reduce pain-related disability, and improve quality of life.

Best for

• Coping with chronic pain

• Reducing pain-related disability

• Improving quality of life

• Anxiety or depression related to chronic illness

• Chronic insomnia

• Fear of movement (kinesiophobia)

Current Evidence

Research supports several approaches, including

• Cognitive behavioral therapy (CBT)

• Acceptance and commitment therapy (ACT)

• Pain neuroscience education

• Mindfulness-based interventions

• Cognitive behavioral therapy for insomnia (CBT-I)

These therapies have consistently been shown to improve coping, physical functioning, sleep, anxiety, depression, and overall quality of life in people living with chronic pain.

Because psychological health and sleep are discussed extensively elsewhere on this website, they are not reviewed further here. See the Psychological Impacts and Sleep Problems articles for more detailed information.

Complementary and Non-Medication Treatments

Because relatively few pain treatments have been studied specifically in hEDS, many people explore complementary therapies in addition to conventional medical care.

Some approaches have moderate scientific support for chronic pain in general, while others are supported primarily by clinical experience or patient reports. This does not necessarily mean they are ineffective—it often reflects the limited amount of research that has been conducted in hEDS.

Best for

• Adjunctive pain management

• Localized muscle or joint pain

• Improving comfort and function

• People seeking additional low-risk treatment options

Current Evidence

Examples include

• Acupuncture

• Massage therapy

• Transcutaneous electrical nerve stimulation (TENS)

• Saline trigger point injections

• Warm-water therapy

• Kinesiology tape

• Infrared heat

• Medical cannabis

• Other complementary approaches

Responses vary considerably from person to person. Some individuals experience meaningful improvement, while others notice little benefit. Most of these treatments should be viewed as complementary to—not replacements for—evidence-based medical care.

A more detailed discussion of these therapies, including the evidence supporting each, is available in the Alternative & Non-medication Treatments article.

Advanced and Specialized Pain Management

Most people with hEDS achieve the greatest improvement through rehabilitation, pacing, treatment of associated conditions, lifestyle modifications, and appropriately selected medications. However, some individuals continue to experience significant pain despite these measures.

Several more specialized treatments may be considered in selected situations. Some are supported by good evidence for specific pain conditions, while others remain investigational in hEDS.

Botulinum Toxin (Botox)

Botulinum toxin (Botox®) is not considered a routine treatment for generalized musculoskeletal pain in hEDS.

Best for

• Chronic migraine

• Cervical dystonia

• Blepharospasm

• Hemifacial spasm

• Other approved neurological conditions

Current Evidence

Botulinum toxin works by temporarily weakening muscles. While this can be beneficial for conditions caused by excessive muscle contraction, it presents a unique concern in hEDS because muscles provide much of the stability for hypermobile joints. Weakening these muscles may increase joint instability and, in some individuals, worsen pain or increase the risk of subluxations and dislocations.

For this reason, botulinum toxin is generally not recommended for treating chronic musculoskeletal pain related to hEDS itself.

Botulinum toxin remains an effective treatment for several conditions that commonly occur alongside hEDS, including chronic migraine, cervical dystonia, blepharospasm, hemifacial spasm, overactive bladder, and certain spasticity disorders. When used for these conditions, treatment decisions should balance the expected benefits against the potential effects on joint stability.

Current evidence does not support botulinum toxin as a treatment for generalized joint pain, ligament instability, or widespread musculoskeletal pain in hEDS.

Corticosteroid Injections

Corticosteroid ("cortisone") injections are commonly used to reduce inflammation within joints, bursae, tendon sheaths, and other soft tissues.

Best for

• Bursitis

• Tendinitis

• Inflammatory arthritis

• Localized inflammatory pain

Current Evidence

In people with hEDS, corticosteroid injections should generally be reserved for clearly inflammatory conditions rather than chronic joint instability or generalized musculoskeletal pain. Repeated corticosteroid injections may weaken already fragile connective tissues and potentially increase the risk of tendon injury.

When used appropriately, corticosteroid injections can provide meaningful short-term relief for carefully selected inflammatory conditions, but the potential benefits should always be weighed against the risks.

Platelet-Rich Plasma (PRP)

Platelet-rich plasma (PRP) therapy involves injecting a concentrated preparation of a person's own platelets into injured tissues with the goal of promoting healing. Because platelets release numerous growth factors involved in tissue repair, PRP has attracted considerable interest as a potential treatment for tendon, ligament, and joint injuries.

Best for

• Selected tendon injuries

• Selected ligament injuries

• Chronic tendinopathy

• Localized musculoskeletal injuries that have not responded to conservative treatment

Current Evidence

Research on PRP has produced mixed results. Some studies have demonstrated improvements in pain and function for certain tendon injuries, while others have found little or no benefit compared with standard treatments. Differences in how PRP is prepared and administered have made results difficult to compare.

Very little research has evaluated PRP specifically in people with hEDS. However, because connective tissue injury is a major contributor to pain in hEDS, PRP has generated considerable interest among both patients and clinicians.

Some physicians experienced in treating hEDS report encouraging results in carefully selected patients, particularly for chronic tendon or ligament injuries that have not responded to rehabilitation. At present, however, there is insufficient evidence to determine which patients are most likely to benefit.

PRP should be considered a promising treatment that requires additional research before it can be routinely recommended for people with hEDS.

Prolotherapy

Prolotherapy involves injecting an irritant solution—most commonly hypertonic dextrose—into ligaments, tendons, or joint capsules with the goal of stimulating the body's natural healing response. Because ligament laxity is central to hEDS, prolotherapy has received considerable attention within the EDS community.

Best for

• Chronic ligament pain

• Joint instability (experimental)

• Chronic tendon injuries (experimental)

Current Evidence

Although prolotherapy has been studied for several musculoskeletal conditions, high-quality evidence remains limited. Research specifically involving people with hEDS is even more limited. Nevertheless, some clinicians who specialize in hypermobility disorders report improvements in pain, stability, and function in selected patients. Many individuals with hEDS have also shared positive experiences, although these reports do not establish that the treatment is effective.

At present, prolotherapy should be considered an emerging treatment with a plausible biological rationale but insufficient scientific evidence to recommend it routinely. Larger, well-designed studies are needed to determine which patients, if any, are most likely to benefit.

Nerve Ablation

Radiofrequency ablation (RFA), cryoablation, and similar procedures interrupt pain signals traveling through specific nerves. These procedures are designed to treat pain arising from a well-defined anatomical structure rather than widespread chronic pain.

Best for

• Localized facet joint pain

• Sacroiliac joint pain

• Selected peripheral nerve pain

• Carefully selected patients with a clearly identified pain generator

Current Evidence

Before nerve ablation is considered, physicians typically perform one or more diagnostic nerve blocks. If temporarily numbing a specific nerve provides substantial pain relief, that nerve may be an appropriate target for ablation.

Because pain in hEDS usually results from multiple overlapping mechanisms rather than a single source, nerve ablation is not appropriate for most people with generalized musculoskeletal pain. However, it may be beneficial for carefully selected individuals whose pain consistently originates from one joint or nerve.

When successful, pain relief may last several months before the treated nerve gradually regenerates. Repeat procedures are sometimes necessary if pain returns.

Although research specific to hEDS is limited, current evidence from other chronic pain conditions suggests that radiofrequency ablation can provide meaningful pain relief for selected mechanical pain conditions.

Emerging Therapies

Research into pain management is advancing rapidly, and several newer therapies may eventually play a role in treating pain associated with hEDS.

Best for

• Individuals interested in emerging treatment options

• People whose pain has not responded to established treatments

Current Evidence

Several therapies are currently under investigation, including

• Suzetrigine, a non-opioid pain medication that selectively blocks NaV1.8 sodium channels involved in pain transmission

• Low-level laser therapy (photobiomodulation)

• Peripheral nerve stimulation

• Additional targeted therapies aimed at reducing abnormal pain signaling

Some of these treatments have shown encouraging early results in other chronic pain conditions, but there is currently insufficient evidence to recommend their routine use in hEDS.

As research continues to improve our understanding of the biological mechanisms responsible for pain in hEDS, future treatments are likely to become increasingly individualized. Rather than treating pain as a single condition, clinicians may eventually tailor therapies to the specific combination of pain mechanisms present in each person.

Surgery

Surgery is sometimes necessary for structural complications of hEDS but is generally considered only after appropriate conservative treatment has failed.

Best for

• Severe recurrent joint instability

• Tendon rupture

• Advanced osteoarthritis

• Selected spinal disorders

• Certain neurological complications, such as craniocervical instability, Chiari malformation, or tethered cord syndrome

Current Evidence

Because connective tissue is inherently fragile in hEDS, surgery presents unique challenges. Tissue fragility, delayed wound healing, increased bruising, joint laxity, and higher recurrence rates following some orthopedic procedures may all affect surgical outcomes.

Whenever possible, surgery should be performed by surgeons who are familiar with hypermobile connective tissue disorders and the unique considerations involved in caring for people with hEDS.

Detailed information about surgical planning, anesthesia, wound healing, and recovery is provided in the Surgical Considerations and Anesthesia articles.

Summary

Pain is one of the most common and disabling features of hypermobile Ehlers-Danlos syndrome, but it rarely has a single cause. Most people experience several pain mechanisms simultaneously, including joint instability, myofascial pain, arthritis, neuropathic pain, small fiber neuropathy, central sensitization, and associated medical conditions. Identifying the combination of mechanisms contributing to an individual's pain is one of the most important steps in developing an effective treatment plan.

Although many treatments have not yet been studied specifically in hEDS, research continues to improve our understanding of why pain occurs and how it can be managed. For most people, the best results come from combining multiple approaches—including rehabilitation, medications, pacing, treatment of associated conditions, and other individualized therapies—rather than relying on a single treatment.

While there is currently no cure for hEDS, many people achieve meaningful improvements in pain, physical function, and quality of life through a comprehensive treatment plan tailored to their individual symptoms and goals.

Low-Dose Naltrexone (LDN)

Low-dose naltrexone (LDN) is an emerging off-label option for people with widespread pain, fatigue, and central sensitization—features common in hEDS.

What is it?

• A very low dose (1.5–4.5 mg) of the drug naltrexone, traditionally used in much higher doses for opioid or alcohol dependence.

• In low doses, it works very differently, modulating pain and inflammation through unique mechanisms.

• Must be obtained at a compounding pharmacy.

• Often is not covered by insurance due to being prescribed off-label. Off-label prescribing is when a healthcare provider prescribes a medication for a use, dose, or population that is not specifically approved by the FDA but is supported by clinical judgment or evidence from research.

How might it help in hEDS?

• LDN is not a standard therapy for hEDS, but it is increasingly used off-label for chronic pain conditions involving central sensitization, such as fibromyalgia, which shares overlapping features with hEDS.

• Proposed mechanisms

  • Inhibition of microglial activation in the central nervous system

  • Toll-like receptor 4 (TLR4) antagonism

  • Reduction of neuroinflammation, possibly helping to dampen pain amplification and brain fog

• Patients often report improvements in

  • Chronic widespread pain

  • Fatigue

  • Sleep quality

  • Cognitive clarity

Evidence base

• Evidence for LDN in hEDS specifically is limited to anecdotal reports and clinician experience.

• However, systematic reviews and meta-analyses show modest benefit in fibromyalgia and related centralized pain conditions, with a good safety profile.

• Most published studies are small or preliminary; high-quality randomized controlled trials in hEDS are currently lacking.

Tolerability

• LDN is generally well-tolerated.

• May have mild and temporary side effects such as vivid dreams or sleep disruption early on.

Formulations

Because commercial manufacturers do not produce tablets in low doses, LDN must be specially prepared by compounding pharmacies. Common formulations include

• Capsules – The most typical option, often filled with microcrystalline cellulose or another neutral filler. Available in precise strengths (e.g., 1.5 mg, 3 mg, 4.5 mg).

• Tablets – Less commonly compounded but sometimes preferred for patients who have trouble swallowing capsules.

• Liquid formulations – Useful for those who require very gradual dose titration (e.g., starting below 1 mg and increasing slowly). Allows for flexible adjustment in 0.1–0.5 mg increments.

• Sublingual drops or lozenges – Occasionally used when gastrointestinal absorption is a concern, though less standardized.

• Topical creams – An experimental option prepared by some pharmacies, typically for patients who cannot tolerate oral forms; evidence is minimal.

Because inactive ingredients vary between pharmacies, patients with sensitivities to dyes, fillers, or excipients (inactive ingredients) may need to request specific formulations. Prescribers can work with the compounding pharmacist to adjust both dosage and formulation to the patient’s needs.

Insurance and Prescription Access

• Insurance coverage is inconsistent. Many insurers consider LDN experimental or non-essential due to its off-label use and will not reimburse for compounded versions.

• Prior authorization or appeal letters from a provider may be required for coverage, and even then, success varies by plan.

• Compounding pharmacies are typically required because low-dose tablets are not commercially manufactured. Prices can range from $30–90/month depending on formulation and location.

• Patients should

  • Ask whether their prescriber can fax the prescription directly to a known compounding pharmacy.

  • Inquire about discount programs or bulk pricing through pharmacies.

  • Save receipts for out-of-pocket costs, which may be reimbursable through FSA/HSA accounts.

• Some patients also find better prices at online or mail-order compounding pharmacies, though quality and licensing should be verified.